irbesartan hydrochlorothiazide zentiva · diabetes mellitus. the package leaflet has been updated...
TRANSCRIPT
Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands
An agency of the European Union
Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000
Irbesartan Hydrochlorothiazide Zentiva Procedural steps taken and scientific information after the authorisation
Application
number
Scope Opinion/
Notification1 issued on
Commission
Decision
Issued2 /
amended
on
Product
Information
affected3
Summary
A31/0101 The European Commission triggered a referral under
Article 31 of Directive 2001/83/EC and requested the
CHMP to assess the impact of nitrosamine impurities
on the benefit-risk balance of valsartan-containing
medicinal products and to issue a recommendation on
whether the relevant marketing authorisations should
be maintained, varied, suspended or revoked. During the CHMP plenary meeting in September 2018,
the scope of the referral has been widened to include
31/01/2019 15/04/2019 Annex II Please refer to the assessment report: Irbesartan Hydrochlorothiazide Zentiva
EMEA/H/A-31/1471/C/783/0101
1 Notifications are issued for type I variations and Article 61(3) notifications (unless part of a group including a type II variation or extension application or a worksharing application). Opinions are issued for all other procedures. 2 A Commission decision (CD) is issued for procedures that affect the terms of the marketing authorisation (e.g. summary of product characteristics, annex II, labelling, package leaflet). The CD is issued within two months of the opinion for variations falling under the scope of Article 23.1a(a) of Regulation (EU) No. 712/2012, or within one year for other procedures. 3 SmPC (Summary of Product Characteristics), Annex II, Labelling, PL (Package Leaflet).
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 2/24
all sartans with a tetrazole group in their molecular
structure (candesartan, irbesartan, losartan,
olmesartan and valsartan).
IG/1076 B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer
05/04/2019 n/a
IAIN/0103 C.I.z - Changes (Safety/Efficacy) of Human and
Veterinary Medicinal Products - Other variation
19/12/2018 15/04/2019 SmPC and PL
IG/1022 B.III.1.a.1 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - New certificate from an already
approved manufacturer
18/12/2018 n/a
T/0100 Transfer of Marketing Authorisation
18/09/2018 08/11/2018 SmPC,
Labelling and
PL
WS/1346 This was an application for a variation following a
worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008. Update of section 4.8 of the SmPC to add ‘anaphylactic
reaction including anaphylactic shock’ to the list of
adverse drug reactions. The PL is updated accordingly.
In addition, the MAH took the opportunity to update
the information on local representatives in Bulgaria
26/07/2018 08/11/2018 SmPC,
Labelling and
PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 3/24
and Germany and to update the product information in
line with the latest QRD template (version 10). C.I.4 - Change(s) in the SPC, Labelling or PL due to
new quality, preclinical, clinical or pharmacovigilance
data
IG/0890 B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer
22/02/2018 n/a
IB/0096/G This was an application for a group of variations. B.II.b.1.a - Replacement or addition of a
manufacturing site for the FP - Secondary packaging
site B.II.b.1.b - Replacement or addition of a
manufacturing site for the FP - Primary packaging site B.II.b.1.e - Replacement or addition of a
manufacturing site for the FP - Site where any
manufacturing operation(s) take place, except
batch-release, batch control, primary and secondary
packaging, for non-sterile medicinal products B.II.b.2.c.2 - Change to importer, batch release
arrangements and quality control testing of the FP -
Including batch control/testing B.II.b.3.a - Change in the manufacturing process of
the finished or intermediate product - Minor change in
the manufacturing process
19/09/2017 08/11/2018 Annex II and PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 4/24
PSUSA/1653/
201609
Periodic Safety Update EU Single assessment -
hydrochlorothiazide / irbesartan
22/06/2017 28/08/2017 SmPC and PL Refer to Scientific conclusions and grounds recommending
the variation to terms of the Marketing Authorisation(s)’ for
PSUSA/1653/201609.
IG/0830 A.7 - Administrative change - Deletion of
manufacturing sites
22/08/2017 n/a
IB/0095 B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF
25/07/2017 n/a
IB/0094/G This was an application for a group of variations. A.4 - Administrative change - Change in the name
and/or address of a manufacturer or an ASMF holder
or supplier of the AS, starting material, reagent or
intermediate used in the manufacture of the AS or
manufacturer of a novel excipient B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF B.I.a.3.a - Change in batch size (including batch size
ranges) of AS or intermediate - Up to 10-fold increase
compared to the originally approved batch size
02/06/2017 n/a
IB/0091/G This was an application for a group of variations. B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF B.I.a.3.a - Change in batch size (including batch size
ranges) of AS or intermediate - Up to 10-fold increase
05/01/2017 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 5/24
compared to the originally approved batch size B.I.a.4.z - Change to in-process tests or limits applied
during the manufacture of the AS - Other variation
IA/0090/G This was an application for a group of variations. B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer
07/11/2016 n/a
N/0089 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
24/09/2015 PL
N/0088 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
17/03/2015 PL
IB/0087 B.I.b.2.e - Change in test procedure for AS or starting
material/reagent/intermediate - Other changes to a
test procedure (including replacement or addition) for
the AS or a starting material/intermediate
19/02/2015 n/a
A31/0075 On 17 April 2013, further to the emergence of new
evidence from the scientific literature on dual RAS
blockade therapy and given the seriousness of the
identified safety concerns, the Italian Medicines
Agency (AIFA) initiated a review under Article 31 of
Council Directive 2001/83/EC, requesting the
22/05/2014 04/09/2014 SmPC and PL For further information please refer to the
Renin-angiotensin-system (RAS)-acting agents Article 31
referral - Assessment report.
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 6/24
Pharmacovigilance Risk Assessment Committee
(PRAC) to issue a recommendation on the benefit-risk
of dual RAS blockade therapy through the combined
use of angiotensin-converting enzyme inhibitors
(ACE-inhibitors), angiotensin II receptor blockers
(ARBs) or aliskiren and to determine whether any
regulatory measures should be taken on the
marketing authorisations of the products involved in
this procedure.
IG/0454 C.I.8.a - Introduction of or changes to a summary of
Pharmacovigilance system - Changes in QPPV
(including contact details) and/or changes in the PSMF
location
17/07/2014 n/a
PSUSA/1653/
201309
Periodic Safety Update EU Single assessment -
hydrochlorothiazide / irbesartan
13/06/2014 n/a PRAC Recommendation - maintenance
IA/0085 B.I.b.1.d - Change in the specification parameters
and/or limits of an AS, starting
material/intermediate/reagent - Deletion of a
non-significant specification parameter (e.g. deletion
of an obsolete parameter)
14/05/2014 n/a
IA/0084 B.II.d.2.a - Change in test procedure for the finished
product - Minor changes to an approved test
procedure
30/04/2014 n/a
IA/0083/G This was an application for a group of variations.
31/03/2014 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 7/24
B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer
IA/0081 B.III.1.a.2 - Submission of a new/updated or deletion
of Ph. Eur. Certificate of Suitability to the relevant Ph.
Eur. Monograph - Updated certificate from an already
approved manufacturer
31/03/2014 n/a
IA/0082 B.II.b.4.a - Change in the batch size (including batch
size ranges) of the finished product - Up to 10-fold
compared to the originally approved batch size
21/03/2014 n/a
N/0079 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
12/03/2014 04/09/2014 PL
IAIN/0078 B.II.b.1.a - Replacement or addition of a
manufacturing site for the FP - Secondary packaging
site
09/10/2013 n/a
IG/0327 C.I.z - Changes (Safety/Efficacy) of Human and
Veterinary Medicinal Products - Other variation
02/08/2013 n/a
II/0069 Update of SmPC sections 4.3, 4.4 and 4.5 to reflect
that the concomitant use of Angiotensin II Receptor
Blockers (ARBs) with aliskiren is contraindicated in
patients with renal impairment and in patients with
27/06/2013 31/07/2013 SmPC, Annex
II, Labelling
and PL
Please refer to the Scientific Discussion "Irbesartan
Hydrochlorothiazide Zentiva-EMEA-H-C-0783-II69".
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 8/24
diabetes mellitus. The Package Leaflet has been
updated accordingly. In addition, the MAH took the
opportunity to align the annexes with the latest QRD
template, to make editorial changes in the annexes
and to introduce the contact details of the local
representative in Croatia in the Package Leaflet. C.I.3.b - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under Article
45/46, or amendments to reflect a Core SPC -
Change(s) with new additional data submitted by the
MAH
IA/0076 A.7 - Administrative change - Deletion of
manufacturing sites
05/06/2013 31/07/2013 Annex II and PL
IB/0072 B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF
06/05/2013 n/a
IAIN/0074 B.III.1.a.3 - Submission of a new or updated Ph. Eur.
Certificate of Suitability to the relevant Ph. Eur.
Monograph - New certificate from a new manufacturer
(replacement or addition)
02/05/2013 n/a
IA/0073 B.II.d.1.d - Change in the specification parameters
and/or limits of the finished product - Deletion of a
non-significant specification parameter (e.g. deletion
of an obsolete parameter
26/04/2013 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 9/24
II/0070 Change in the specifications limits range for the active
substance Irbesartan. B.I.b.1.f - Change in the specification parameters
and/or limits of an AS, starting
material/intermediate/reagent - Change outside the
approved specifications limits range for the AS
25/04/2013 n/a
IA/0071 B.I.a.3.a - Change in batch size (including batch size
ranges) of AS or intermediate - Up to 10-fold increase
compared to the currently approved batch size
22/04/2013 n/a
IAIN/0068 C.I.z - Changes (Safety/Efficacy) of Human and
Veterinary Medicinal Products - Other variation
03/01/2013 n/a
IA/0067 B.II.b.4.a - Change in the batch size (including batch
size ranges) of the finished product - Up to 10-fold
compared to the currently approved batch size
20/12/2012 n/a
IA/0066 A.7 - Administrative change - Deletion of
manufacturing sites
03/12/2012 n/a
T/0063 Transfer of Marketing Authorisation
10/09/2012 12/11/2012 SmPC,
Labelling and
PL
Transfer of the Marketing Authorisation to sanofi-aventis
groupe, France.
IAIN/0065 B.II.b.1.a - Replacement or addition of a
manufacturing site for the FP - Secondary packaging
site
30/10/2012 n/a
IB/0064/G This was an application for a group of variations.
15/10/2012 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 10/24
B.I.b.2.c - Change in test procedure for AS or starting
material/reagent/intermediate - Other changes to a
test procedure for a reagent, which does not have a
significant effect on the overall quality of the AS B.I.b.2.e - Change in test procedure for AS or starting
material/reagent/intermediate - Other changes to a
test procedure (including replacement or addition) for
the AS or a starting material/intermediate
II/0060 This type II variation application concerns an update
of section 4.4 of the SmPC to include a warning on the
risk of 'acute myopia' and 'secondary acute
angle-closure glaucoma' associated with the use of
hydrochlorothiazide. Further, section 4.8 of the SmPC
has been updated to include the two ADRs 'acute
myopia' and 'secondary acute angle-closure
glaucoma' and the Package Leaflet has been updated
accordingly. In addition, the MAH has taken the
opportunity to implement editorial changes to the
annexes and to revise the annexes in line with the
latest QRD template (version 8.1). C.I.4 - Variations related to significant modifications of
the SPC due in particular to new quality, pre-clinical,
clinical or pharmacovigilance data
24/05/2012 27/06/2012 SmPC, Annex
II, Labelling
and PL
A total of six cases of ‘Acute Myopia’ and ‘Secondary Acute
Angle-Closure Glaucoma’ were identified following a
comprehensive literature review by the MAH. Two of them
were considered related to the combination of irbesartan and
HCTZ. Five cases reported bilateral ‘acute angle-closure
glaucoma’ and one reported ‘acute myopia’ and ‘perimacular
oedema’. It is acknowledged that concomitant drugs and
medical history are potential confounding factors in all cases
identified, but nevertheless a role of HTCZ in these cases
cannot be ruled out. Although the number of reported cases of ‘acute
angle-closure glaucoma’ and ‘acute myopia’ is very small,
the CHMP was of the view that this information should be
reflected as a warning in the SmPC due to the seriousness of
these ADRs that can lead to important visual disability, and
the fact that other sulfa-derivated drugs have also been
reported to cause the ADRs bilateral ‘acute myopia’ and
‘acute angle-closure glaucoma’. Therefore, it was agreed to add the following warning to the
SmPC: “‘Acute Myopia and Secondary Acute Angle-Closure
Glaucoma: sulfonamide drugs or sulfonamide derivative
drugs can cause an idiosyncratic reaction, resulting in
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 11/24
transient myopia and acute angle-closure glaucoma. While
hydrochlorothiazide is a sulfonamide, only isolated cases of
acute angle-closure glaucoma have been reported so far with
hydrochlorothiazide. Symptoms include acute onset of
decreased visual acuity or ocular pain and typically occur
within hours to weeks of drug initiation. Untreated acute
angle-closure glaucoma can lead to permanent vision loss.
The primary treatment is to discontinue drug intake as
rapidly as possible. Prompt medical or surgical treatments
may need to be considered if the intraocular pressure
remains uncontrolled. Risk factors for developing acute
angle-closure glaucoma may include a history of sulfonamide
or penicillin allergy.” The overall benefit-risk balance for the combination
irbesartan + HCTZ remains unchanged.
IB/0062 B.II.d.2.d - Change in test procedure for the finished
product - Other changes to a test procedure (including
replacement or addition)
21/06/2012 n/a
IAIN/0061 A.1 - Administrative change - Change in the name
and/or address of the MAH
03/04/2012 27/06/2012 SmPC,
Labelling and
PL
IB/0059/G This was an application for a group of variations. B.II.d.2.d - Change in test procedure for the finished
product - Other changes to a test procedure (including
replacement or addition) B.II.d.2.d - Change in test procedure for the finished
product - Other changes to a test procedure (including
replacement or addition)
13/03/2012 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 12/24
R/0049 Renewal of the marketing authorisation.
20/10/2011 27/02/2012 Based on the CHMP review of the available information and
on the basis of a re-evaluation of the benefit risk balance, the
CHMP was of the opinion that the quality, safety and efficacy
of this medicinal product continues to be adequately and
sufficiently demonstrated and therefore considered that the
benefit risk profile of Irbesartan Hydrochlorothiazide
Winthrop continues to be favourable. The CHMP recommended the renewal of the Marketing
Authorisation for Irbesartan Hydrochlorothiazide Winthrop,
subject to the conditions as laid down in Annex II to the
Opinion. The CHMP was also of the opinion that the renewal
can be granted with unlimited validity. The renewal required no amendments to the terms of the
Community Marketing Authorisation
IA/0058 B.I.b.2.a - Change in test procedure for AS or starting
material/reagent/intermediate - Minor changes to an
approved test procedure
20/02/2012 n/a
IB/0055 C.I.3.a - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under A 45/46,
or amendments to reflect a Core SPC - Changes with
NO new additional data are submitted by the MAH
16/02/2012 27/06/2012 SmPC and PL
IAIN/0057/G This was an application for a group of variations. A.2.a - Administrative change - Change in the
(invented) name of the medicinal product for CAPs B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
06/02/2012 27/06/2012 SmPC, Annex
II, Labelling
and PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 13/24
the currently approved pack sizes B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
the currently approved pack sizes B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
the currently approved pack sizes B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
the currently approved pack sizes B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
the currently approved pack sizes B.II.e.5.a.1 - Change in pack size of the finished
product - Change in the number of units (e.g. tablets,
ampoules, etc.) in a pack - Change within the range of
the currently approved pack sizes
IA/0056/G This was an application for a group of variations. B.II.b.3.a - Change in the manufacturing process of
the finished product - Minor change in the
manufacturing process of an immediate release solid
oral dosage form or oral solutions B.II.b.4.a - Change in the batch size (including batch
size ranges) of the finished product - Up to 10-fold
compared to the currently approved batch size
19/01/2012 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 14/24
IB/0053 B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF
13/01/2012 n/a
IB/0052 B.I.a.3.a - Change in batch size (including batch size
ranges) of AS or intermediate - Up to 10-fold increase
compared to the currently approved batch size
11/01/2012 n/a
IB/0054 B.I.a.3.z - Change in batch size (including batch size
ranges) of AS or intermediate - Other variation
04/01/2012 n/a
WS/0171 This was an application for a variation following a
worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008. Update of Summary of Product Characteristics C.I.3.a - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under A 45/46,
or amendments to reflect a Core SPC - Changes with
NO new additional data are submitted by the MAH
22/09/2011 24/10/2011 SmPC This type IB variation concerns an update of SmPC sections
4.6 and 5.3, upon request by CHMP, with agreed wording
regarding fertility. It is unknown whether irbesartan or its metabolites are
excreted in human milk. Available
pharmacodynamic/toxicological data in rats have shown
excretion of irbesartan or its metabolites in milk. Fertility and reproductive performance were not affected in
studies of male and female rats even at oral doses of
irbesartan causing some parental toxicity (from 50 to 650
mg/kg/day), including mortality at the highest dose. No
significant effects on the number of corpora lutea, implants,
or live fetuses were observed. Irbesartan did not affect
survival, development, or reproduction of offspring. Studies
in animals indicate that the radiolabeled irbesartan is
detected in rat and rabbit fetuses. This application was submitted following a worksharing
procedure according to Article 20 of Commission Regulation
(EC) No 1234/2008.
WS/0147 This was an application for a variation following a 21/07/2011 07/09/2011 SmPC and PL This type II variation concerns an update of section 4.5 of the
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 15/24
worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008. This was an application for a variation following a
worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008. C.I.3.b - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under A 45/46,
or amendments to reflect a Core SPC - Change(s) with
new additional data submitted by the MAH C.I.3.b - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under Article
45/46, or amendments to reflect a Core SPC -
Change(s) with new additional data submitted by the
MAH
SmPC, upon request by the CHMP following the assessment
of PSUR 9, to include information about the potential
interaction between hydrochlorothiazide and
carbamazepine. Concomitant use of carbamazepine and
hydrochlorothiazide has been associated with the risk of
symptomatic hyponatraemia. Therefore, electrolytes should
be monitored during concomitant use, and if possible,
another class of diuretics should be used. The Package
Leaflet has been updated accordingly. In addition, the MAH
took the opportunity to put the annexes in line with the latest
QRD template (version 7.3.1). This application was submitted as a Type II variation
following a worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008.
WS/0074 This was an application for a variation following a
worksharing procedure according to Article 20 of
Commission Regulation (EC) No 1234/2008. Update of Summary of Product Characteristics and
Package Leaflet C.I.3.a - Implementation of change(s) requested
following the assessment of an USR, class labelling, a
PSUR, RMP, FUM/SO, data submitted under A 45/46,
or amendments to reflect a Core SPC - Changes with
NO new additional data are submitted by the MAH
14/04/2011 16/06/2011 SmPC and PL This type IB variation concerns an update of section 4.8 of
the SmPC with the ADR ‘jaundice’, upon request by the CHMP
following the assessment of irbesartan PSUR 15 and FU2
020.1. The Package Leaflet has been updated accordingly. In
addition, the MAH took the opportunity to make some
editorial changes in the SmPC and Package Leaflet. This application was submitted following a worksharing
procedure according to Article 20 of Commission Regulation
(EC) No 1234/2008.
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 16/24
IA/0048 A.7 - Administrative change - Deletion of
manufacturing sites
27/05/2011 n/a
IA/0047 B.I.b.2.a - Change in test procedure for AS or starting
material/reagent/intermediate - Minor changes to an
approved test procedure
04/05/2011 n/a
IA/0044/G This was an application for a group of variations. A.4 - Administrative change - Change in the name
and/or address of a manufacturer or supplier of the
AS, starting material, reagent or intermediate used in
the manufacture of the AS A.4 - Administrative change - Change in the name
and/or address of a manufacturer or supplier of the
AS, starting material, reagent or intermediate used in
the manufacture of the AS
11/04/2011 n/a
IA/0045 C.I.9.e - Changes to an existing pharmacovigilance
system as described in the DDPS - Changes in the
major contractual arrangements with other persons or
organisations involved in the fulfilment of
pharmacovigilance obligations and described in the
DD
08/04/2011 n/a Annex II
IB/0046 B.I.b.1.z - Change in the specification parameters
and/or limits of an AS, starting
material/intermediate/reagent - Other variation
06/04/2011 n/a
T/0043 Transfer of Marketing Authorisation
24/11/2010 06/01/2011 SmPC,
Labelling and
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 17/24
PL
IA/0042/G This was an application for a group of variations. C.I.9.h - Changes to an existing pharmacovigilance
system as described in the DDPS - Other change(s) to
the DDPS that does not impact on the operation of the
pharmacovigilance system C.I.9.c - Changes to an existing pharmacovigilance
system as described in the DDPS - Change of the
back-up procedure of the QPPV
28/10/2010 n/a Annex II
IA/0041 B.III.2.a.1 - Change of specification('s) of a former
non Pharmacopoeial substance to comply with the Ph.
Eur. or with a national pharmacopoeia of a Member
State - AS
06/07/2010 n/a
IB/0040 B.I.a.2.e - Changes in the manufacturing process of
the AS - Minor change to the restricted part of an
ASMF
10/06/2010 n/a
IB/0039 B.I.b.2.e - Change in test procedure for AS or starting
material/reagent/intermediate - Other changes to a
test procedure (including replacement or addition) for
the AS or a starting material/intermediate
19/05/2010 n/a
N/0038 To change the phone number of the Slovak local
representative in the Package Leaflet. Furthermore
the Marketing Authorisation Holder took this
opportunity to make linguistic amendments to the
Dutch and French Package Leaflets.
27/04/2010 n/a PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 18/24
Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
IA/0037/G This was an application for a group of variations. C.I.9.b - Changes to an existing pharmacovigilance
system as described in the DDPS - Change in the
contact details of the QPPV C.I.9.h - Changes to an existing pharmacovigilance
system as described in the DDPS - Other change(s) to
the DDPS that does not impact on the operation of the
pharmacovigilance system
22/03/2010 n/a Annex II
II/0033 Update of SPC section 4.8 upon request by CHMP
following the assessment of the renewal of the
reference medicinal product CoAprovel
(EMEA/H/C/000222/R/0108), with respect to the
introductory paragraph and the estimate of the overall
percentage of treated patients to experience adverse
reactions. Update of Summary of Product Characteristics
17/12/2009 04/02/2010 SmPC This Type II variation was submitted in order to update
section 4.8 (Undesirable effects) of the SmPC based on a
request from the CHMP following the assessment of the
renewal of the reference medicinal product CoAprovel to
provide information on adverse reactions according to the EU
SmPC Guideline (October 2005), as well as to include a
general description on what are the most serious and/or
most frequently occurring adverse drug reactions. In support
to this application, the MAH submitted a review of the
Integrated Summary of Safety (ISS) as well as cumulative
data from placebo-controlled hypertensive trials
CV131-037,-038,-039, and -040. The updated section 4.8 includes now the following
paragraph: Irbesartan/hydrochlorothiazide combination: Among 898 hypertensive patients who received various
doses of irbesartan/hydrochlorothiazide (range: 37.5
mg/6.25 mg to 300 mg/25mg) in placebo-controlled trials,
29.5% of the patients experienced adverse reactions. The
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 19/24
most commonly reported ADRs were dizziness (5.6%),
fatigue (4.9%), nausea/vomiting (1.8%), and abnormal
urination (1.4%). In addition, increases in blood urea
nitrogen (BUN) (2.3%), creatine kinase (1.7%) and
creatinine (1.1%) were also commonly observed in the trials. Table 1 gives the adverse reactions observed from
spontaneous reporting and in placebo-controlled trials.
IB/0036 IB_38_c_Change in test procedure of finished product
- other changes
07/01/2010 n/a
II/0034 Update of Summary of Product Characteristics (SPC)
section 4.5 and Package Leaflet section 2 regarding
information on the interaction of hydrochlorothiazide
(HCTZ) with cholestyramin and colestipol resins. In
particular to provide further guidance in the SPC to
physicians on the recommended time between the
administration of irbesartan + HCTZ and
cholestyramin and colestipol resins. Update of Summary of Product Characteristics and
Package Leaflet
19/11/2009 21/12/2009 SmPC and PL With this application, SPC section 4.5 the existing statement
regarding an interaction with colestyramine and colestipol
resins has been amended indicating that
irbesartan + hydrochlorothiazide should be taken at least
one hour before or four hours after these medications. A literature search was performed by the MAH to identify
studies leading to a drug interaction between irbesartan,
hydrochlorothiazide and cholestyramine. In a study with ten
healthy adult male subjects evaluating appropriate dosing
schedules of cholestyramine to minimize its effect on
absorption, the investigators reported that the best dosing
schedule for cholestyramine is 4 hours after
hydrochlorothiazide (Hunninghake and Hibbard, 1986). On
the other hand, it has been recommended that the
administration of cholestyramine or colestipol have to be
separated from the time of other medications (e.g. HCTZ) by
1-2 hours to minimize their effects on the absortion (Lamrini
et al 1997; Hunninghake et al 1982).
IB/0035 IB_13_b_Change in test proc. for active substance -
other changes (replacement/addition)
02/12/2009 n/a
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 20/24
N/0032 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
09/10/2009 n/a PL
II/0031 Change of the manufacturing site of irbesartan and as
a consequence a change in the batch size of this active
substance. Change(s) to the manufacturing process for the active
substance
24/09/2009 08/10/2009
IA/0030 IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
08/07/2009 n/a
IB/0026 IA_07_a_Replacement/add. of manufacturing site:
Secondary packaging site IB_07_c_Replacement/add. of manufacturing site: All
other manufacturing operations ex. batch release IA_07_b_01_Replacement/add. of manufacturing
site: Primary packaging site - Solid forms
23/06/2009 n/a PL
IA/0029 IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
22/06/2009 n/a
IA/0028 IA_08_b_02_Change in BR/QC testing - repl./add.
manuf. responsible for BR - incl. BC/testing
10/06/2009 n/a PL
IA/0027 IA_32_a_Change in batch size of the finished product
- up to 10-fold
20/05/2009 n/a
N/0025 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
14/05/2009 n/a PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 21/24
II/0023 Update of SPC sections 2, 4.1, 4.2, 4.3, 4.4, 4.8, 5.1,
5.2 and 6.1 as well as the package leaflet to align the
Product Information of Irbesartan Hydrochlorotihazide
Winthrop with the Product Information of the
reference product CoAprovel. Update of Summary of Product Characteristics and
Package Leaflet
19/03/2009 17/04/2009 SmPC and PL The SPC and Package Leaflet of Irbesartan
Hydrochlorothiazide Winthrop have been aligned with the
Product Information of the reference product CoAprovel as
approved with the renewal procedure.
IB/0024 IB_10_Minor change in the manufacturing process of
the active substance
17/04/2009 n/a
II/0022 The MAH applied for an update of the SPC sections 4.3
and 4.6 as well as PL section 2 to implement the CHMP
recommendation on a harmonised labelling relating to
the use of Angiotensin II Receptor Antagonists during
pregnancy and lactation. Furthermore, minor
typographical changes have been introduced to SPC
section 4.4. Update of Summary of Product Characteristics and
Package Leaflet
19/02/2009 27/03/2009 SmPC and PL Available data regarding use of AIIRAs during lactation have
been assessed. There are no concrete data to support the
contraindication of use of AIIRAs during breast-feeding. All AIIRA agents were found in the milk of lactating rats but
no human data about their transfer into breast milk are
available. There is only a theoretical presumption of low
transport according to their high plasma protein binding and
low oral availability. A harmonised wording recommending
an alternative treatment with better established safety
profiles during breast-feeding, especially while nursing a
newborn or preterm infant, has been included in the section
4.6 of the SPC and section 2 of the PL. Consequently, the existing contraindication for lactation has
been deleted.
II/0021 Update of Detailed Description of the
Pharmacovigilance System Changes to QPPV
22/01/2009 06/03/2009 Annex II The Detailed Description of the Pharmacovigilance System
has been updated (Version 3.0) to reflect the change of the
Qualified Person for Pharmacovigilance (QPPV) as well as to
notify other changes to the DDPS performed since the last
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 22/24
Update of DDPS (Pharmacovigilance)
approved version. Consequently, Annex II has been updated
using the standard text including the new version number of
the agreed DDPS.
IB/0020 IB_10_Minor change in the manufacturing process of
the active substance IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
18/08/2008 n/a
IA/0019 IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
29/07/2008 n/a
II/0014 Update of Summary of Product Characteristics and
Package Leaflet The MAH applied for an update of the SPC sections 4.3,
4.4, and 4.6 as well as PL section 2 to implement the
CHMP recommendation on a harmonised labelling
relating to the use of ACE inhibitors and Angiotensin II
Receptor Antagonists during pregnancy. Update of Summary of Product Characteristics and
Package Leaflet
24/04/2008 10/06/2008 SmPC and PL Cooper’s study published in the NEJM in June 2006 identified
a signal of increased risk of congenital malformations,
particularly cardiac defects after exposure to ACE inhibitors
during the first trimester of pregnancy. Since the role of
confounding factors such as diabetes and hypertension
cannot be accurately defined based on the available data, the
teratogenic potential of ACE inhibitors is not demonstrated,
even though data suggest that such exposure cannot be
considered as safe and should be avoided. There are fewer data regarding the risks associated with first
trimester exposure to Angiotensin II receptor antagonists
(AIIRAs) than for ACE inhibitors. Nevertheless, there is no
evidence that the risk is lower for AIIRAs, and it is considered
that any conclusions on ACE inhibitors are also valid for
AIIRAs. Therefore, the existing contraindication for the 2nd and 3rd
trimester of pregnancy remained, but a harmonised wording
regarding pregnancy across the class was introduced.
IB/0016 IA_07_a_Replacement/add. of manufacturing site:
Secondary packaging site 08/05/2008 n/a PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 23/24
IB_07_c_Replacement/add. of manufacturing site: All
other manufacturing operations ex. batch release IA_07_b_01_Replacement/add. of manufacturing
site: Primary packaging site - Solid forms IA_08_b_02_Change in BR/QC testing - repl./add.
manuf. responsible for BR - incl. BC/testing
IB/0018 IB_42_a_01_Change in shelf-life of finished product -
as packaged for sale
07/05/2008 n/a SmPC
IB/0017 IB_10_Minor change in the manufacturing process of
the active substance IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
25/04/2008 n/a
IA/0015 IA_09_Deletion of manufacturing site
03/04/2008 n/a
IA/0013 IA_09_Deletion of manufacturing site
13/02/2008 n/a
IA/0012 IA_09_Deletion of manufacturing site
14/12/2007 n/a
N/0011 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
07/12/2007 n/a PL
IB/0009 IB_10_Minor change in the manufacturing process of
the active substance
21/09/2007 n/a
IA/0010 IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
20/09/2007 n/a
N/0008 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
22/08/2007 n/a PL
Irbesartan Hydrochlorothiazide Zentiva EMA/285635/2019 Page 24/24
IB/0007 IA_07_a_Replacement/add. of manufacturing site:
Secondary packaging site IB_07_c_Replacement/add. of manufacturing site: All
other manufacturing operations ex. batch release IA_07_b_01_Replacement/add. of manufacturing
site: Primary packaging site - Solid forms IA_08_b_02_Change in BR/QC testing - repl./add.
manuf. responsible for BR - incl. BC/testing
22/08/2007 n/a Annex II and PL
IB/0005 IB_07_c_Replacement/add. of manufacturing site: All
other manufacturing operations ex. batch release IA_07_b_01_Replacement/add. of manufacturing
site: Primary packaging site - Solid forms IA_08_b_02_Change in BR/QC testing - repl./add.
manuf. responsible for BR - incl. BC/testing
07/06/2007 n/a PL
IB/0004 IB_33_Minor change in the manufacture of the
finished product
21/05/2007 n/a
IA/0006 IA_32_b_Change in batch size of the finished product
- downscaling down to 10-fold
15/05/2007 n/a
N/0001 Minor change in labelling or package leaflet not
connected with the SPC (Art. 61.3 Notification)
14/05/2007 n/a PL
IA/0003 IA_11_a_Change in batch size of active substance or
intermediate - up to 10-fold
23/03/2007 n/a